JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2025
·Vol. 29
·期 15
·e70744
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IF 4.2
Xuan Li,Shiyu Meng,Jiayi Liu,Meixian Sun,Mao Zhou,Fengtao Ji,Yu Hong
In this study, we investigated the therapeutic potential of Berberine (BBR), an anti‐inflammatory agent capable of penetrating the blood–brain barrier, for mitigating postoperative cognitive dysfunction (POCD) in aged mice. BBR was administered at a dose of 10 mg/kg daily for 2 weeks and significantly improved cognitive impairments induced by surgical and anaesthesia‐related factors. Specifically, BBR markedly suppressed glial cell activation and reduced levels of pro‐inflammatory cytokines such as tumour necrosis factor alpha (TNF‐α) and interleukin‐1 beta (IL‐1β). Additionally, it alleviated oxidative stress markers and lipid accumulation. Using network pharmacology analysis, we demonstrated that BBR modulates neuroinflammation, oxidative processes and lipid metabolism by inhibiting the phosphorylation of the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (Akt) pathway. Furthermore, extended research revealed that BBR upregulated the expression of PPAR‐ γ mRNA, suggesting a neuroprotective mechanism via regulation of the PI3K‐Akt pathway. These findings support the potential application of BBR as a therapeutic agent for managing POCD in elderly populations.
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JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Chaoyu Huang,Chen Qian,Zongxian Li,Yuanyuan Qin,Wuning Mo,Faquan Lin
Ethnopharmacological relevance Rosa roxburghii is an ethnic medicinal herb. Folk medicine collections have documented its nourishing and strengthen effects. It has been used to improve reproductive health, but scientific evidence supporting its efficacy and mechanisms remains limited. Aim of this study Endocrine-disrupting chemicals, such as di-(2-ethylhexyl) phthalate (DEHP), are known to impair male reproductive health. This study aims to investigate the protective effects of raw Rosa roxburghii juice (RRJ) on DEHP-induced reproductive toxicity in mice and elucidates its underlying mechanisms. Materials and methods Using a DEHP-induced murine model of reproductive damage, we evaluated the effects of RRJ on sperm quality, testicular histopathology, reproductive endocrine function, oxidative stress, inflammation, apoptosis, and DNA damage. Network pharmacology analysis was performed to identify the active components, targets, and mechanisms underlying the therapeutic effects of Rosa Roxburghii . Results Our data demonstrated that RRJ significantly improved sperm quality, alleviated testicular atrophy, restored endocrine disorders, and mitigated oxidative stress, inflammation, and apoptosis in testicular tissues. Additionally, RRJ reduced testicular and sperm DNA damage, as evidenced by decreased γ-H2AX expression and DNA fragmentation index. Network pharmacology analysis identified quercetin, apigenin, luteolin, kaempferol, eriodictyol, and ellagic acid as the key bioactive compounds in RRJ, with the PI3K/AKT signaling pathway playing a crucial role in its therapeutic effects. Western blotting confirmed that RRJ reversed DEHP-induced suppression of the PI3K/AKT pathway. Conclusions This study demonstrates that RRJ protects against DEHP-induced reproductive toxicity through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, mediated in part by the PI3K/AKT signaling pathway. This work provides the first comprehensive evidence of the protective effects of Rosa roxburghii against male reproductive system damage and its underlying mechanisms.
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Advanced Science
·
2025
·
IF 14.1
Yunzhi Liu,Cuicui Huang,Min Luo,Wenfu Lu,Baifeng Zhang,Lu Bai,Shuyue Zheng,Yanan Tan,Shanshan Li,Huali Wang,Lanqi Gong,Xinyuan Guan
Nasopharyngeal carcinoma (NPC) is one of the common head and neck cancers in Southern China and Southeast Asia. Although current studies have adequately characterized the tumor microenvironment (TME) of NPC, little attention has been paid to how cell-cell interactions within the TME promote tumorigenesis. In this study, it is found that C1q + tumor-associated macrophages (TAMs) are significantly enriched in NPC tumors. Moreover, both enriched C1q + TAMs and elevated C1q expression are associated with the progression and poor prognosis in NPC patients. In vitro and in vivo studies demonstrate that C1q directly boosts the malignancy and stemness of tumor cells. Mechanistically, C1q activates the Phosphatidylinositol-3-kinase (PI3K)/AKT pathway through interacting with GPR17, a member of the G protein-coupled receptor family, thereby inducing DNA hypermethylation of tumor cells to promote tumor development. It is further proved that DNA hypermethylated NPC cells induced by C1q elicited the immunosuppressive phenotype of TAMs. Targeted blockade of C1q with a neutralizing antibody restricts NPC progression in the humanized mouse model. It is assumed that the differentiation of C1q + TAMs possibly acquired both M1 and M2 polarization conditions. These findings provide new insights into the cellular communication in the TME of NPC and may have important applications for the development of new targeted therapies.
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LIFE SCIENCES
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2025
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IF 5.1
Qing Li,Mei Zhou,Ying Yang,Yangming Jiang,Chao Chen,Enming Hu,Jialin Chen,Daoping Wang
Overexpression of EphB3 has been documented across various cancers and essential for cell proliferation, survive and metastasis, making it a valuable therapeutic target. In this study, a series of novel penta-1,4-dien-3-one and quinoxaline conjugates were designed and synthesized using pharmacophore fusion strategies to explore potential EphB3 inhibitors. CCK-8 experiments revealed significant anti-cancer activity of most newly synthesized compounds against hepatocellular carcinoma (HCC). Among them, compound W8 displaying the highest inhibitory activity against MHCC97H (IC 50 = 1.87 μM), which arrests MHCC97H cells in the G0/G1 phase and induces apoptosis. Furthermore, compound W8 suppresses tumor growth in an MHCC97H xenograft model in vivo by suppressing phosphorylation level of EphB3 and down-regulating the SRC-AKT signaling pathway, leading to a dose-dependent reduction in tumor volumes and weights, with a 40 mg/kg dose achieving decreases of 68.4 % and 65.3 %, respectively. Given its ability to modulate EphB3 signaling, W8 represents a promising lead compound for further drug development, particularly for cancers characterized by EphB3 overexpression, and may offer new opportunities for targeted therapy in precision oncology.
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INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
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2025
·Vol. 57
·期 1
·14
·
IF 5.8
Shuang Dou,Zhijun Li,Boyao Zheng,Zhenyu Ren,Hai Wang,Qing Zuo,Fang Fang,Yuehong Zhuang
The present study investigates the molecular mechanisms of peripheral nerve regeneration by examining the ROCK/PI3K/Akt/GSK3β pathway's role in promoting morphological and functional recovery after peripheral nerve injury (PNI). Using a mouse sciatic nerve crush (SNC) injury model and a dorsal root ganglion (DRG) explant axotomy model, mice and DRG were divided the experimental (treated with DMSO) group, Y27632 group (treated with ROCK inhibitor Y27632), Y + LY group (treated with Y27632 + PI3K inhibitor LY294002), and Y + LY + SB group (treated with Y27632 + LY294002 + GSK3β inhibitor SB216763). Immunofluorescence was used to assess axon density, diameter, myelin thickness and Schwann cell proliferation, while retrograde tracing with cholera toxin subunit B evaluated peripheral-to-central reconnection. Behavioral tests measured functional recovery, and in DRG explants, axon regeneration length and growth cone size were quantified. Protein expression analysis of RhoA, ROCK, PI3K, Akt, GSK3β, and their phosphorylated forms was conducted on day 3 post-axotomy, both in vivo and in vitro . Additionally, RSC96 Schwann cell migration and proliferation were evaluated using scratch assays and EdU staining. Results showed that ROCK inhibition with Y27632 significantly enhanced axonal regeneration, growth cone expansion, retrograde transport, and reinnervation of acetylcholine receptors and Merkel cells, and promoted Schwann cell proliferation and RSC96 migration, leading to thicker myelin sheaths after SNC. These changes mitigated gastrocnemius muscle atrophy, improved muscle strength, gait, and thermal/tactile sensitivity. Co-treatment with LY294002 blocked these effects, but adding SB216763 restored them. Protein analysis indicated that ROCK inhibition increased phosphorylated PI3K, Akt and GSK3β, whereas PI3K inhibition reduced GSK3β phosphorylation. These findings suggested that ROCK inhibition promotes axon regeneration and remyelination after PNI by enhancing PI3K/Akt phosphorylation and suppressing GSK3β activity, highlighting the therapeutic potential of targeting the ROCK/PI3K/Akt/GSK3β pathway for peripheral nerve repair.
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MOLECULAR NEUROBIOLOGY
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2025
·Vol. 63
·期 1
·39
·
IF 4.3
Hu Yingying,Qian Rengcheng,He Yifeng,Gao Qiqi,Wang Xun,Lin Huilin,Lin Wei,Fang Yu,Zhu Jianghu,Wang Xingyun,Nan Yan,Lin Zhenlang
Neonatal hypoxic-ischemic brain damage (HIBD) is a devastating disease for which no treatments that effectively mitigate severe neurological consequences exist. Recent studies have shown that costunolide (COS), a well-known bioactive sesquiterpene lactone, possesses potent anti-inflammatory and neuroprotective properties, but its efficacy in the context of HIBD remains unclear. Here, we investigated the neuroprotective effects of COS in both in vivo and in vitro models of hypoxic-ischemic (HI) brain injury. In vivo, we found that COS intervention following a HI event dramatically reduced the brain infarction volume, ameliorated the inflammatory response, promoted histological recovery, and improved the prognosis. To explore the underlying molecular mechanisms, we performed an in vitro study and reported that COS protected PC12 cells from oxygen‒glucose deprivation (OGD) insult by reducing the levels of inflammatory mediators. Furthermore, COS activated the PI3K/AKT signaling pathway to suppress NF-κB and inflammation. In contrast, the PI3K inhibitor LY294002 reversed these therapeutic benefits. Our findings reveal that COS is a promising neuroprotective agent and could be used to treat HIBD and other related brain injuries.
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TISSUE & CELL
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2025
·
IF 2.5
Yanfei Yang,Lili Yang,Yabin Li,Yanfen Wang
Background The gut microbiota is essential for the bidirectional communication between the gut and the brain. However, its specific role and underlying mechanisms in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis remain largely unclear. Methods An anti-NMDAR encephalitis model was induced by GluN1 peptide immunization, and brain histopathology was assessed by hematoxylin-eosin staining. Behavioral performance was assessed through the Y-maze and open field tests. Flow cytometry was employed to quantify T follicular helper (Tfh) and T follicular regulatory (Tfr) cell populations. Enzyme-linked immunosorbent assay and western blot were used to assess inflammatory cytokines and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway-related protein levels, respectively. 16S rRNA sequencing and Helicobacter rodentium gavage (1.5 mL, 1×10¹¹ CFU/mL) were used to assess microbiota composition and bacterial function. Results 16S rRNA sequencing revealed a trend toward reduced gut microbial diversity in anti-NMDAR encephalitis mice. Helicobacter rodentium colonization further exacerbated behavioral deficits and inflammatory cell infiltration in the cerebral cortex. This was accompanied by a marked increase in tumor necrosis factor alpha (TNF-α) and interleukin (IL)-21 levels and a reduction in IL-10 concentrations in both cerebrospinal fluid and serum. Moreover, the Tfh/Tfr cell ratio was further elevated following Helicobacter rodentium exposure. Targeted suppression of the PI3K/AKT pathway with LY294002 significantly restored Tfh/Tfr balance and alleviated neurobehavioral impairments and cortical inflammation. Conclusion Helicobacter rodentium exacerbates anti-NMDAR encephalitis by inducing PI3K/AKT-mediated Tfh/Tfr imbalance, highlighting a potential therapeutic target in autoimmune encephalitis.
研究领域:
神经免疫学
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微生物组研究
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自身免疫性疾病
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分子信号通路
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炎症生物学
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Results in Chemistry
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2025
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IF 4.2
Dongqing He,Dongjun Liu,Zhuoyan Wu,Ruiguang Xiao,Wenjie Ruan,Zeqiang Lin,Qiuxia Chen,Chanling Yuan,Qiong Wu,Wenjie Mei
Acne is a chronic inflammatory skin disease that is highly prevalent in adolescents, and its recurrent flare-ups can affect facial aesthetics, severely impacting adolescents' mental health and quality of life. Screening for safer, more effective fruit acid molecules for daily acne treatment is crucial. This work examined potential mandelic acid derivatives. In a zebrafish model, mandelic acid showed a 78.17 % rate of inflammatory cell aggregation, outperforming supramolecular salicylic acid (86.96 % aggregation) at the same concentration. In a P. acnes -induced cell model, MMP9 protein expression was significantly upregulated in the model group. After treatment with mandelic acid, MMP9 expression decreased by 72.84 % compared to the model group, a better effect than that of supramolecular salicylic acid (36.78 %). Further mechanistic investigations indicate that mandelic acid may inhibit the PI3K/AKT signaling pathway activated by P. acnes , thereby blocking MAPK signaling and modulating MMP9 protein production, thereby averting the development of NLRP3 inflammatory vesicles. Mandelic acid has a favourable safety profile and notable anti-inflammatory properties, which can be further harnessed to mitigate acne in sensitive skin demographics, offering a novel approach to acne treatment.
研究领域:
皮肤病学
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炎症研究
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分子生物学
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药理学
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Molecular Medicine Reports
·
2017
·Vol. 17
·期 2
·3062-3068
·
IF 1.692
Kai‑Fei Li,Chun‑Min Kang,Xiao‑Feng Yin,Hai‑Xia Li,Zhuo‑Yu Chen,Yao Li,Qiong Zhang,Yu‑Rong Qiu
Ginsenoside Rh2 (G‑Rh2), the main bioactive component in American ginseng, is known to exert a wide variety of biological activities. Accumulating evidence suggests that G‑Rh2 inhibits cell proliferation and induces apoptosis of tumor cells. However, the possible mechanism through which G‑Rh2 exerts its action on malignant glioma cells have not been completely elucidated. The findings of the present study demonstrated that G‑Rh2 decreased the viability of glioma cells in a dose‑ and time‑dependent manner, and induced cell cycle arrest. G‑Rh2‑induced cell cycle arrest was accompanied by the downregulation of cyclin‑dependent kinase 4 and Cyclin E. In addition, G‑Rh2 markedly reduced the expression of total‑ RAC‑α serine/threonine‑protein kinase (Akt) and the levels of phosphorylated‑Akt. These findings provide mechanistic details of how G‑Rh2 acts on glioma cells and suggest that G‑Rh2 may function as a potential anti‑cancer drug for glioma treatment.
研究领域:
肿瘤学
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细胞生物学
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药理学
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Oxidative Medicine and Cellular Longevity
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2021
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IF 6.543
Yanxia Ma,Yu Liu,Linxin Teng,En Luo,Dekang Liu,Fuqiong Zhou,Kaiyuan Wang,Weiping Chen,Lei Bi
Lung cancer has become the leading cause of cancer-related death worldwide. Oxidative stress plays important roles in the pathogenesis of lung cancer. Many natural products show antioxidative activities in cancer treatment. Zi Shen decoction (ZSD) is a classic prescription for the treatment of lung disease. However, its effect on lung cancer lacks evidence-based efficacy. In this study, we investigated the anticancer effects of ZSD on lung cancer in vivo and in vitro. Our results showed that oral administration of ZSD suppressed the Lewis lung cancer (LLC) growth in a subcutaneous allograft model and promoted necrosis and inflammatory cell infiltration in the tumor tissues. Furthermore, ZSD not only inhibited tumor cell proliferation and migration but also induced cell apoptosis in lung cancer cells. PI3K/AKT signaling is well characterized in response to oxidative stress. The bioinformatics analysis and western blot assays suggested that ZSD decreased the enzyme activity of PI3K and AKT in vivo and in vitro. We also found that the AKT/GSK-3β/β-catenin pathway medicated anticancer effect of ZSD in lung cancer cells. In conclusion, we demonstrate for the first time that ZSD possesses antitumor properties, highlighting its potential use as an alternative strategy or adjuvant treatment for lung cancer therapy.
研究领域:
肿瘤学
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药理学
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分子生物学
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中医
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Evidence-based Complementary and Alternative Medicine
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2022
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IF 2.65
Haijun Gao,Yan Zhang,Xiaojin Mo,Lele Huo,Yanping Luo,Ting Zhang,Xingming Ma,Wei Hu,Tao Jing
Background. Liver cancer, particularly hepatocellular carcinoma (HCC), is the fourth leading cause of cancer-related death worldwide. Sorafenib is a crucial drug for the treatment of advanced HCC, but it is difficult to meet the challenge of increasing clinical demands due to its severe side effects and drug resistance. Hence, development of novel antitumor drugs is urged. Previous studies showed that pseudolaric acid B (PAB) could reduce the expression of protein kinase B (PKB/Akt), a downstream effector of Notch signaling, facilitating cell apoptosis in HCC. The disruption of Notch signaling was verified to exacerbate malignant progression and drug resistance, however, the antitumor effect of PAB on Notch signaling in HCC remains unclear. Thus, this study aims to investigate the anti-HCC effect of PAB in association with the regulation of Notch1/Akt signaling. Methods. CCK-8 assay and transwell assay were used to examine the cell proliferation and invasion in Huh7 cells after treatment with PAB and a Notch inhibitor DAPT. Moreover, the cell cycle of Huh7 cells after treatment with PAB was analyzed using flow cytometry. Finally, the changes of Notch1, Jagged1, Hes1, and Akt expression at the protein and mRNA level in Notch1/Akt signaling in Huh7 cells after treatment with PAB and DAPT were analyzed using immunofluorescence assay and real-time qPCR. Results. The proliferation rate of Huh7 cells exposed to PAB of 0.5, 1, 2, 4, 8, 10, 20, 40, 80, 100, and 200 μmol/L revealed a time-and dose-dependent decrease in vitro, showing cell cycle arrest at G2/M phase . Furthermore, compared with the untreated group, at the concentration of 40 μmol/L, the proliferation rate and invasion rate of Huh7 cells in PAB, DAPT, and PAB-DAPT combination (PAB + DAPT) group were significantly decreased , but the PAB + DAPT showed no synergistic antiproliferation and anti-invasion effect in comparison with PAB treatment alone . In addition, compared with the untreated group, PAB and DAPT alone significantly downregulated the expression of Notch1, Jagged1, Hes1, Akt mRNA, or/and protein in Huh7 cells , but there was no significant difference in synergistic downregulated effect between the PAB + DAPT group and the PAB group . Conclusion. PAB can suppress proliferation and invasion of HCC cells through downregulating the expression of Notch1/Akt signaling protein and mRNA, and may be a potential novel antitumor drug candidate for the clinical treatment of HCC in the future.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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药理学
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JOURNAL OF PHARMACOLOGICAL SCIENCES
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2014
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IF 2.114
Jing Lu,Duanping Sun,Si Gao,Ying Gao,Jiantao Ye,Peiqing Liu
Autophagy is a highly regulated and multi-step biological process that serves to remove damaged cytoplasmic components and organelles. It has been suggested that the activation of autophagy may be a promising therapeutic strategy for cancer treatment by triggering cell death. In this study, we reported that cyclovirobuxine D (CVB-D), an alkaloid component in a traditional Chinese herb, could induce autophagy in the MCF-7 human breast cancer cell line. CVB-D inhibited the viability of MCF-7 cells in a concentration- and time-dependent manner. Activation of autophagy was characterized by transmission electron microscopy, monodansylcadaverine staining, and expression of autophagy marker microtubule-associated protein 1 light chain 3 (LC3). After CVB-D treatment, a clear accumulation of autophagosomes was observed accompanied with elevated LC3 fluorescent puncta. Western blot analysis revealed that CVB-D significantly promoted the conversion from LC3-I to LC3-II and the expression of autophagy-related protein 5 (ATG5), which are both essential for autophagosome formation. On the other hand, CVB-D–induced autophagy and decrease in cell viability could be blocked by 3-methyladenine, a well-established autophagy inhibitor. Moreover, CVB-D attenuated the phosphorylation of Akt and mTOR, two pivotal suppressors in autophagy pathways. These findings shed new light on the pharmacological actions and mechanism of CVB-D and may support the potential utility of autophagy inducers in cancer treatment.
研究领域:
肿瘤学
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药理学
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细胞生物学
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